Plasticity Of Intrinsic Excitability Research Articles

Biphasic Somatic A-Type K+ Channel Downregulation Mediates Intrinsic Plasticity in Hippocampal CA1 Pyramidal Neurons

Since its original description, the induction of synaptic long-term potentiation (LTP) has been known to be accompanied by a lasting increase in the intrinsic excitability (intrinsic plasticity) of hippocampal neurons. Recent evidence shows that dendritic excitability can be enhanced by an activity-dependent decrease in the activity of A-type K+ channels. In the present manuscript, we examined the role of A-type K+ channels in regulating intrinsic excitability of CA1 pyramidal neurons of the hippocampus after synapse-specific LTP induction. In electrophysiological recordings we found that LTP induced a potentiation of excitability which was accompanied by a two-phased change in A-type K+ channel activity recorded in nucleated patches from organotypic slices of rat hippocampus. Induction of LTP resulted in an immediate but short lasting hyperpolarization of the voltage-dependence of steady-state A-type K+ channel inactivation along with a progressive, long-lasting decrease in peak A-current density. Blocking clathrin-mediated endocytosis prevented the A-current decrease and most measures of intrinsic plasticity. These results suggest that two temporally distinct but overlapping mechanisms of A-channel downregulation together contribute to the plasticity of intrinsic excitability. Finally we show that intrinsic plasticity resulted in a global enhancement of EPSP-spike coupling.

Synaptic Mechanisms for Plasticity in Neocortex

Sensory experience and learning alter sensory representations in cerebral cortex. The synaptic mechanisms underlying sensory cortical plasticity have long been sought. Recent work indicates that long-term cortical plasticity is a complex, multicomponent process involving multiple synaptic and cellular mechanisms. Sensory use, disuse, and training drive long-term potentiation and depression (LTP and LTD), homeostatic synaptic plasticity and plasticity of intrinsic excitability, and structural changes including formation, removal, and morphological remodeling of cortical synapses and dendritic spines. Both excitatory and inhibitory circuits are strongly regulated by experience. This review summarizes these findings and proposes that these mechanisms map onto specific functional components of plasticity, which occur in common across the primary somatosensory, visual, and auditory cortices.

TRIP8b Splice Variants Form a Family of Auxiliary Subunits that Regulate Gating and Trafficking of HCN Channels in the Brain

Hyperpolarization-activated cyclic nucleotide-regulated (HCN) channels, which generate the I(h) current, mediate a number of important brain functions. The HCN1 isoform regulates dendritic integration in cortical pyramidal neurons and provides an inhibitory constraint on both working memory in prefrontal cortex and spatial learning and memory in the hippocampus. Altered expression of HCN1 following seizures may contribute to the development of temporal lobe epilepsy. Yet the regulatory networks and pathways governing HCN channel expression and function in the brain are largely unknown. Here, we report the presence of nine alternative N-terminal splice forms of the brain-specific cytoplasmic protein TRIP8b and demonstrate the differential effects of six isoforms to downregulate or upregulate HCN1 surface expression. Furthermore, we find that all TRIP8b isoforms inhibit channel opening by shifting activation to more negative potentials. TRIP8b thus functions as an auxiliary subunit that provides a mechanism for the dynamic regulation of HCN1 channel expression and function.

Lack of DREAM Protein Enhances Learning and Memory and Slows Brain Aging

Memory deficits in aging affect millions of people and are often disturbing to those concerned. Dissection of the molecular control of learning and memory is paramount to understand and possibly enhance cognitive functions. Old-age memory loss also has been recently linked to altered Ca(2+) homeostasis. We have previously identified DREAM (downstream regulatory element antagonistic modulator), a member of the neuronal Ca(2+) sensor superfamily of EF-hand proteins, with specific roles in different cell compartments. In the nucleus, DREAM is a Ca(2+)-dependent transcriptional repressor, binding to specific DNA signatures, or interacting with nucleoproteins regulating their transcriptional properties. Also, we and others have shown that dream mutant (dream(-/-)) mice exhibit marked analgesia. Here we report that dream(-/-) mice exhibit markedly enhanced learning and synaptic plasticity related to improved cognition. Mechanistically, DREAM functions as a negative regulator of the key memory factor CREB in a Ca(2+)-dependent manner, and loss of DREAM facilitates CREB-dependent transcription during learning. Intriguingly, 18-month-old dream(-/-) mice display learning and memory capacities similar to young mice. Moreover, loss of DREAM protects from brain degeneration in aging. These data identify the Ca(2+)-regulated "pain gene" DREAM as a novel key regulator of memory and brain aging.

Firing first: compensatory changes in K+ channel knockout mice preserve excitability but not synaptic scaling

Synaptic potentials are severely filtered as they propagate through the dendritic tree. As action potentials are usually generated in the axon, how can distal synapses influence neuronal output? In hippocampal CA1 pyramidal neurons, distal synapses cope with this situation by producing progressively larger synaptic currents at increasing distance from the soma (Magee & Cook, 2000). An increase in the number of AMPA receptors with distance from the soma is thought to be responsible for this amplitude normalization (distance-dependent synaptic scaling) (Andrasfalvy & Magee, 2001). The question then arises: how is this gradient set-up; how does the distal synapse come to know of its disadvantaged location and express more AMPA receptors? In this issue of The Journal of Physiology, Andrasfalvy and colleagues (Andrasfalvy et al. 2008) investigate the possibility that action potentials, initiated in the axon but propagating back into the dendrites (bAPs), provide feedback to the synapses about their location. In the primary apical dendrite of hippocampal CA1 pyramidal neurons, bAPs attenuate as they travel away from the soma (Spruston et al. 1995). This attenuation can by reduced by pharmacologically blocking A-type K+ channels, which increase several-fold in density with distance from the soma (Hoffman et al. 1997). Greater back-propagation is also observed upon genetic down-regulation or deletion of the A-type K+ channel α subunit Kv4.2, establishing this protein as the molecular identity of dendritic A-type currents (IA) in these neurons (Fig. 1) (Kim et al. 2005; Chen et al. 2006). In the present work, the authors compared miniature excitatory postsynaptic current (mEPSC) amplitudes in proximal and distal dendritic recordings from Kv4.2−/− and wild-type (WT) mice. Consistent with previous data from this group, in WT mice, distal mEPSCs were larger than proximal. If bAPs inform the synapse of its location, larger bAPs in Kv4.2−/− mice might then be expected to exhibit smaller mEPSCs at distal locations compared to those from WT. Indeed, distance-dependent scaling was lost in Kv4.2−/− mice, predominately through a reduction in distal mEPSC amplitudes. Figure 1 Targeted rescue of intrinsic excitability in Kv4.2−/− mice Previous studies using dominant negative Kv4.2 constructs to acutely decrease its function, in both neocortical and hippocampal pyramidal neurons, have demonstrated a prominent role of Kv4.2 in regulating membrane excitability (e.g. input resistance, AP threshold, half-width and frequency) (Kim et al. 2005; Yuan et al. 2005). Recently, however, recordings from cortical pyramidal neurons of Kv4.2−/− mice revealed no major effects of Kv4.2 elimination on firing properties compared to WT. The rescue of firing properties appears to come about through increased densities of other types of K+ channels to compensate for the loss in IA (Nerbonne et al. 2008). In hippocampal neurons, Andrasfalvy et al. also find only modest changes in membrane excitability of Kv4.2−/− mice. Although there is also some evidence for compensation via increased expression of other K+ channel subunits in Kv4.2−/− hippocampal neurons (Chen et al. 2006), in the present report, the authors also find changes in tonic and phasic GABA currents. Blocking these inhibitory currents revealed increased membrane excitability in knockout hippocampal pyramidal neurons compared to WT. In addition to demonstrating important roles for dendritic K+ channels in distance-dependent scaling, the study by Andrasfalvy et al. raises a number of questions. First, are bAPs themselves responsible for setting up the distance-dependent scaling or are other factors that also depend on Kv4.2 expression involved? If bAPs are responsible, what signalling cascades are involved? Finally, distance-dependent synaptic scaling is reminiscent of another form of plasticity that promotes network stability, synaptic homeostasis. In synaptic homeostasis, excitatory input strength throughout the neuron is negatively regulated by extended periods of high activity or positively by low activity. How are these two homeostatic mechanisms related and does synaptic homeostasis, unlike distance-dependent scaling, persist in Kv4.2−/− neurons? It is tempting to compare the acute effects of Kv4.2 down-regulation in CA1 neurons of organotypic slice cultures (Kim et al. 2005) with the more prolonged and complete elimination in the knockout presented here (Fig. 1). Interestingly, while both manipulations decrease IA, resulting in greater back-propagation and changes in mEPSC amplitudes; membrane excitability and firing patterns, altered with acute Kv4.2 knockdown, are preserved in Kv4.2−/− mice through the compensatory mechanisms detailed above. Under the same developmental and homeostatic influences, however, the distance-dependent gradient of synaptic strength is lost in knockout mice. This privileged rescue of intrinsic excitability (a cellular phenomenon lacking spatial specificity) with apparent disregard for the normal spatial distribution of synaptic weights, runs counter to the notion that compensatory mechanisms would act to preserve, as much as possible, the neuron's computational power. Rather these results indicate that the plasticity of intrinsic excitability may act as an important information storage system distinct from synaptic plasticity (Zhang & Linden, 2003).

Plasticity of Intrinsic Excitability during Long-Term Depression Is Mediated through mGluR-Dependent Changes inIhin Hippocampal CA1 Pyramidal Neurons

Bidirectional changes in synaptic strength are the proposed cellular correlate for information storage in the brain. Plasticity of intrinsic excitability, however, may also be critical for regulating the firing of neurons during mnemonic tasks. We demonstrated previously that the induction long-term potentiation was accompanied by a persistent decrease in CA1 pyramidal neuron excitability (Fan et al., 2005). We show here that induction of long-term depression (LTD) by 3 Hz pairing of back-propagating action potentials with Schaffer collateral EPSPs was accompanied by an overall increase in CA1 neuronal excitability. This increase was observed as an increase in the number of action potentials elicited by somatic current injection and was caused by an increase in neuronal input resistance. After LTD, voltage sag during hyperpolarizing current injections and subthreshold resonance frequency were decreased. All changes were blocked by ZD7288 (4-ethylphenylamino-1,2-dimethyl-6-methylaminopyrimidinium chloride), suggesting that a physiological loss of dendritic h-channels was responsible for the increase in excitability. Furthermore, block of group 1 metabotropic glutamate receptors (mGluRs) or protein kinase C prevented the increase in excitability, whereas the group 1 mGluR agonist DHPG [(RS)-3,5-dihydroxyphenylglycine] mimicked the effects. We conclude that 3 Hz synaptic stimulation downregulates I(h) via activation of group 1 mGluRs and subsequent stimulation of protein kinase C. We propose these changes as part of a homeostatic and bidirectional control mechanism for intrinsic excitability during learning.

Plasticity and stability in neuronal output via changes in intrinsic excitability: it's what's inside that counts

The nervous system faces an extremely difficult task. It must be flexible, both during development and in adult life, so that it can respond to a variety of environmental demands and produce adaptive behavior. At the same time the nervous system must be stable, so that the neural circuits that produce behavior function throughout the lifetime of the animal and that changes produced by learning endure. We are only beginning to understand how neural networks strike a balance between altering individual neurons in the name of plasticity, while maintaining long-term stability in neural system function. The balance of this plasticity and stability in neural networks undoubtedly plays a critical role in the normal functioning of the nervous system. While mechanisms of synaptic plasticity have garnered extensive study over the past three decades, it is only recently that more attention has been turned to plasticity of intrinsic excitability as a key player in neural network function. This review will focus on this emerging area of research that undoubtedly will contribute a great deal to our understanding of the functionality of the nervous system.

Long-term plasticity of intrinsic excitability: learning rules and mechanisms.

Spatio-temporal configurations of distributed activity in the brain is thought to contribute to the coding of neuronal information and synaptic contacts between nerve cells could play a central role in the formation of privileged pathways of activity. Synaptic plasticity is not the exclusive mode of regulation of information processing in the brain, and persistent regulations of ionic conductances in some specialized neuronal areas such as the dendrites, the cell body, and the axon could also modulate, in the long-term, the propagation of neuronal information. Persistent changes in intrinsic excitability have been reported in several brain areas in which activity is elevated during a classical conditioning. The role of synaptic activity seems to be a determinant in the induction, but the learning rules and the underlying mechanisms remain to be defined. We discuss here the role of synaptic activity in the induction of intrinsic plasticity in cortical, hippocampal, and cerebellar neurons. Activation of glutamate receptors initiates a long-term modification in neuronal excitability that may represent a parallel, synergistic substrate for learning and memory. Similar to synaptic plasticity, long-lasting intrinsic plasticity appears to be bidirectional and to express a certain level of input or cell specificity. These nonsynaptic forms of plasticity affect the signal propagation in the axon, the dendrites, and the soma. They not only share common learning rules and induction pathways with the better-known synaptic plasticity such as NMDA receptor dependent LTP and LTD, but also contribute in synergy with these synaptic changes to the formation of a coherent engram.